mp-062
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High Sensitivity C-Reactive Protein

Policy Number: MP-062

Latest Review Date: June 2019

Category: Laboratory

Policy Grade: Active Policy but no longer scheduled for regular literature reviews and updates.

DESCRIPTION OF PROCEDURE OR SERVICE:

C-reactive protein (CRP) is a nonspecific acute phase reactant produced by the liver as a marker to monitor inflammatory processes, such as infection and autoimmune diseases. Studies suggest the association of low-level chronic inflammation during atherogenesis, and thus measurement of C-reactive protein has been investigated in various settings of atherosclerotic cardiovascular disease. This included patients with known atherosclerotic cardiovascular disease, patients with risk factors for cardiovascular disease, and as a general risk assessment tool for cardiovascular disease. Conventional methodologies for the measurement of C-reactive protein in acute inflammatory diseases have a detection limit of three to five mg/L. In the setting of the low levels of chronic inflammation in otherwise healthy individuals, this level of detection is not adequate. To be used as a risk assessment tool, a greater precision of lower levels of C-reactive protein is needed such that the range of values collected in epidemiologic studies can be subdivided into quartiles and quintiles; in this way, the data from large epidemiologic studies can be applied to individual patients. It is theorized that the increased sensitivity of high-sensitivity C-reactive protein (hs-CRP) tests should be able to detect that activity as a marker for atherosclerotic cardiovascular disease.

POLICY:

High sensitivity C-reactive protein (hs-CRP) may be considered medically necessary as a marker of increased risk for cardiovascular disease when the patient has documented:

  • clinical coronary heart disease (CAD); and/or
  • diabetes mellitus; and/or
  • hyperlipidemia; and/or
  • peripheral arterial disease; and/or
  • abdominal aortic aneurysm; and/or
  • symptomatic carotid artery disease; and/or
  • first degree family member with history of early (males before age 55 and females before age 65) cardiovascular event

Measurement of high sensitivity C-reactive protein is considered not medically necessary and investigational when performed for screening or first line testing.

KEY POINTS:

Policy was updated with literature review performed on May 24, 2019.

Half of all heart attacks occur among persons without overt hyperlipidemia. Ridker, et al, in the Women’s Health Study, stated that high-sensitivity C-reactive protein (hs-CRP) was the most significant predictor of the risk of cardiovascular events of 12 plasma measures evaluated in this study. In the Physicians’ Health Study, also by Ridker, et al, the observation that C-reactive protein testing combined with standard lipid screening appears to provide an improved method of detecting subclinical atherosclerosis. This marker may lead to better clinical identification of patients who might benefit from primary prevention and for whom the cost-to-benefit ratio for long-term use of statins would be improved.

In a study published by Zacho et al 10,276 persons from a general population cohort were studied, including 1786 in whom ischemic heart disease developed and 741 in whom ischemic cerebrovascular disease developed. Another 31,992 persons were examined from a cross-sectional general population study, of whom 2521 had ischemic heart disease and 1,483 had ischemic cerebrovascular disease. A sample of 2,238 patients with ischemic heart disease with 4,474 control subjects and 612 patients with ischemic cerebrovascular disease with 1,224 control subjects were compared. Levels of high-sensitivity CRP and conducted genotyping for four CRP polymorphisms and two apolipoprotein E polymorphisms were measured.

The results of the Zacho study found that the risk of ischemic heart disease and ischemic cerebrovascular disease was increased by a factor of 1.6 and 1.3, respectively, in persons who had CRP levels above three mg per liter, as compared with persons who had CRP levels below one mg per liter. Genotype combinations of the four CRP polymorphisms were associated with an increase in CRP levels of up to 64%, resulting in a theoretically predicted increased risk of up to 32% for ischemic heart disease and up to 25% for ischemic cerebrovascular disease. However, these genotype combinations were not associated with an increased risk of ischemic vascular disease. In contrast, apolipoprotein E genotypes were associated with both elevated cholesterol levels and an increased risk of ischemic heart disease. It was concluded that polymorphisms in the CRP gene are associated with marked increases in CRP levels and thus with a theoretically predicted increase in the risk of ischemic vascular disease. However, these polymorphisms are not in themselves associated with an increased risk of ischemic vascular disease.

An article published in the Archives of Internal Medicine studied nearly 16,000 adults in a prospective study using 19 novel risk factors as predictors. Of the 19 markers studied, lipoprotein-associated phospholipase A, vitamin B, interleukin 6, and soluble thrombomodulin added the most to the prediction of coronary heart disease. The findings suggested that routine measurement of these novel markers is not warranted for risk assessment.

There is not sufficient information to justify the use of hs-CRP in routine care without having adequate tools and guidelines to incorporate hs-CRP into routine clinical decision-making. Researchers have started to address these needs with studies such as Kozan et al, in which hs-CRP was used to reclassify individuals into clinically relevant risk categories, and The Reynolds Risk Score, which offers clinicians an alternative risk prediction model for cardiovascular disease in women that includes hs-CRP. Questions have been raised about the reclassification study because of lack of an additional step of evaluating the impact of the reclassification. Also, including revascularization as an end-point has been raised as an issue with the article on the Reynolds Risk Score. In addition, these potential tools for using hs-CRP measurements have not yet become widely disseminated nor have they been incorporated into existing clinical guidelines concerning cardiac risk assessment.

Summary of Evidence

The existing observational evidence establishes that CRP is an independent predictor of cardiovascular disease across a wide spectrum of patient populations. The evidence also suggests that using CRP as a component of a risk assessment toll will result in a more accurate cardiac risk predictions. There is no scientific literature that directly tests the hypothesis that measurement of C-reactive protein to assess CHD risk results in improved patient outcomes.

Elevated serum C-reactive protein (CRP) is a predictor of coronary heart disease in population samples. We studied the contribution of the simultaneous presence (joint effects) of elevated CRP and the classic as well as some new risk factors on acute coronary events. Elevated CRP enhances the risks attributed to classic coronary risk factors. The evidence is sufficient to prove the necessity of high sensitivity C-reactive protein (hs-CRP) as a marker of increased risk for cardiovascular disease when the patient has certain comorbidities.

Practice Guidelines and Position Statements

In 2018, the United States Preventive Services Task Force (USPSTF) issued recommendations about the use of nontraditional risk factors in the risk assessment for cardiovascular heart disease (CHD). They concluded with regard to hs-CRP testing that there are insufficient data to assess the balance of benefits and harms of using CRP to screen asymptomatic men and women to prevent CHD events.

In 2009, the Canadian Cardiovascular Society issued guidelines covering the treatment of dyslipidemia and the prevention of Atherosclerotic cardiovascular disease (ASCVD). Screening hs-CRP was recommended in men older than 50 years and women older than 60 years who were at intermediate risk by the Framingham Risk Score (FRS; 10 to 20 percent at 10 years) and who would otherwise not qualify for lipid-lowering therapy because of an LDL <3.5 mmol/L (135 mg/dL). These individuals were felt to benefit from screening with hs-CRP due to a potential benefit from statin therapy in those with elevated hs-CRP levels.

The 2003 CDC/AHA statement on markers of inflammation and CVD included the following conclusions concerning the use of serum hs-CRP measurements in determining cardiovascular risk:

  • If used, hs-CRP should be measured twice, optimally two weeks apart, with the values averaged. Values should be reported in mg/L.
  • Low-, intermediate-, and high-risk CRP values were defined as <1, 1 to 3, and >3 mg/L. A value above 10 mg/L should be repeated after an interval of at least two weeks and the patient evaluated for infection or inflammation.
  • In patients at intermediate risk for ASCVD (10 to 20 percent at 10 years by the FRS), hs-CRP may help direct further evaluation and therapy for primary prevention, at the discretion of the clinician.

U.S. Preventative Services Task Force

Not applicable

KEY WORDS:

C-reactive protein, high-sensitivity C-reactive protein, hs-CRP, CRP, cardiovascular risk assessment, ASCVD, Atherosclerotic cardiovascular disease

APPROVED BY GOVERNING BODIES:

This guidance is intended to provide device manufacturers and FDA staff with updated recommendations concerning 510(k) submissions for various types of assays for C-Reactive Protein (CRP). The document is a revision of “Guidance for Industry: In Vitro Diagnostic C-Reactive Protein Immunological Test System,” issued on July 20, 1998. It is updated to address issues associated with the development of hsCRP (high sensitivity CRP) and cCRP (cardiac CRP) assays. These types of CRP assays have significantly lower limits of detection, and functional sensitivities that may be used to support new clinical uses of CRP quantitation. This document now includes discussion of how you should support indications for use claims of cCRP “for the evaluation of patients with coronary disease and coronary syndromes” in premarket submissions, including how you should assess different ranges of measurement, based on indications for use. Additionally, we provide recommendations for limitations of CRP test interpretation based on the non-specific nature of CRP elevations in blood.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP contracts: FEP does not consider investigational if FDA approved and will be reviewed for medical necessity. Special benefit consideration may apply. Refer to member’s benefit plan.

CURRENT CODING:

CPT codes:

86141

C-reactive protein, high sensitivity

REFERENCES:

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  2. American Heart Association. Recommendations for the use of high-sensitivity C-reactive protein (Cardio CRP™) testing. www.questdiagnostics.com/hcp/topics/ahacdc/ahacdc.html.
  3. Arruda-Olson AM, Enriquez-Sarano M, Bursi F, et al. Left ventricular function and C-reactive protein levels in acute myocardial infarction. Am J Cardiol, April 2010; 105(7): 917-921.
  4. Cao JJ, Arnold AM, Manolio TA, et al. Association of carotid artery intima-media thickness, plaques, and C-reactive protein with future cardiovascular disease and all-cause mortality: The cardiovascular health study. Circulation 2007; 116: 32-38.
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  6. Delhaye C, Maluenda G, Wakabayashi K, et al. Long-term prognostic value of preprocedural C-reactive protein after drug-eluting stent implantation. Am J Cardiol, March 2010; 105(6): 826-832.
  7. Ecklund C, Kivimaki M, Islam MS, et al. C-reactive protein genetics is associated with carotid artery compliance in men in The Cardiovascular Risk in Young Finns Study. Atherosclerosis 2008; 196(2): 841-848.
  8. Folsom AR, Chambless LE, Ballantyne CM, Coresh J, et al. An assessment of incremental coronary risk prediction using C-reactive protein and other novel risk markers: The atherosclerosis risk in communities study. Archives of Internal Medicine, July 2006; 166(13): 1368-1373.
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  10. Grundy Scott M, Becker D, Clark LT, et al. Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002; 106: 3143.
  11. Horowitz, Gary L. and Beckwith, Bruce A. C-reactive protein in the prediction of cardiovascular disease, New Eng Jour of Med, August 2000, Vol. 343, No. 7, pp. 512-513.
  12. Kervinen H, Palosuo T, Manninen V, Tenkanen L, Vaarala O, Mänttäri M. Joint effects of C-reactive protein and other risk factors on acute coronary events. Am Heart J. 2001;141(4):580
  13. Kivimaki M, Lawlor DA, Smith GD, et al. Variants in the CRP gene as a measure of lifelong differences in average C-reactive protein levels: the Cardiovascular Risk in Young Finns Study, 1980-2001. Am J Epidemiol 2007; 166(7): 760-764.
  14. Koenig W, Löwel H, Baumert J, Meisinger C. C-reactive protein modulates risk prediction based on the Framingham Score: implications for future risk assessment: results from a large cohort study in southern Germany. Circulation. 2004;109(11):1349.
  15. Libby, Peter. Atherosclerosis: The new view. Scientific American, May 2002, pp. 47-55.
  16. McCormack JP and Allan GM. Measuring hsCRP—An important part of a comprehensive risk profile or a clinically redundant practice? PLoS Medicine, February 2010, Vol. 7, Issue 2.
  17. McMurray JJ, Kjekshus J, et al. Effects of statin therapy according to plasma high-sensitivity C-reactive protein concentration in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA): A retrospective analysis. Circulation, December 2009; 120(22): 2188-2196.
  18. Mora S, Musunuru K and Blumenthal RS. The clinical utility of high-sensitivity C-reactive protein in cardiovascular disease and the potential implication of JUPITER on current practice guidelines. Clinical chemistry 2009; 55(2): 219-228.
  19. Munford, Robert S. Statins and the acute-phase response, New Eng Jour of Med, June 2001, Vol. 344, No. 26, pp. 2016-2018.
  20. The National Heart, Lung, and Blood Institute (NHLBI)-National Institutes of Health. Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III), May 2001.
  21. Olsen MH, Hansen TW, Christensen MK, et al. N-terminal pro-brain natriuretic peptide, but not high sensitivity C-reactive protein, improves cardiovascular risk prediction in the general population. Eur Heart J 2007; 28(11): 1374-1381.
  22. Padayachee L, Rodseth RN and Biccard BM. A meta-analysis of the utility of C-reactive protein in predicting early, intermediate-term and long term mortality and major adverse cardiac events in vascular surgical patients. Anaesthesia, April 2009; 64(4): 416-424.
  23. Park DW, Yun SC, Lee JY, et al. C-reactive protein and the risk of stent thrombosis and cardiovascular events after drug-eluting stent implantation. Circulation, November 2009; 120(20): 1987-1995.
  24. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, Rifai N, Smith SC Jr, Taubert K, Tracy RP, Vinicor F. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107(3):499.
  25. Perry TE, Muehlschlegel JD, Liu KY, et al. Preoperative C-reactive protein predicts long-term mortality and hospital length of stay after primary, nonemergent coronary artery bypass grafting. Anesthesiology, March 2010; 112(3): 607-613.
  26. Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation. 2001;103(13):1813.
  27. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, Macfadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ, JUPITER Trial Study Group. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009;373(9670):1175. Epub 2009 Mar 28.
  28. Ridker, Paul M., Hennekens, Charles H., et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women, New Eng Jour of Med, March 2000, Vol. 342, No. 12, pp. 836-843.
  29. Ridker, Paul M., Rifai, Nader, et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events, New Eng Jour of Med, June 2001, Vol. 344, No. 26, pp. 1959-1965.
  30. Ridker, Paul M., Stampfer, Meir J., and Rifai, Nader. Novel risk factors for systemic atherosclerosis: A comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease, JAMA, May 2001, Vol. 285, No. 19, pp. 2481-2485.
  31. Ridker PM, Buring JE, Rifai N, et al. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA 2007; 297(6): 611-619.
  32. Ridker PM, Danielson E, Fonseca FA, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: A prospective study of the JUPITER trial. Lancet, April 2009; 373(9670): 1175-1182.
  33. Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-Reactive protein. NEJM, November 2008, Vol. 359, No. 21, pp. 2195-2207.
  34. Ridker PM, Wilson PW, Grundy SM. Should C-reactive protein be added to metabolic syndrome and to assessment of global cardiovascular risk? Circulation. 2004;109(23):2818.
  35. Sattar N, Murray HM, McConnachie A, et al. C-reactive protein and prediction of coronary heart disease and global vascular events in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Circulation 2007; 115(8): 981-989.
  36. US Preventive Services Task Force, Curry SJ, Krist AH, Owens DK, Barry MJ, Caughey AB, Davidson KW, Doubeni CA, Epling JW Jr, Kemper AR, Kubik M, Landefeld CS, Mangione CM, Silverstein M, Simon MA, Tseng CW, Wong JB. Risk Assessment for Cardiovascular Disease With Nontraditional Risk Factors: US Preventive Services Task Force Recommendation Statement. JAMA. 2018;320(3):272.
  37. Weng CM, Chou CH, Huang YY, et al. Increased C-reactive protein is associated with future development of diabetes mellitus in essential hypertensive patients. Heart Vessels, September 2010; 25(5): 386-391.
  38. Yang EY, Nambi V, Tang Z, et al. Clinical implications of JUPITER (Justification for the Use of statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) in a U.S. population insights from the ARIC (Atherosclerosis Risk in Communities) study. J Am Coll Cardiol, December 2009; 54(25): 2388-2395.
  39. Zacho J, Tybjaerg-Hansen A, Jensen JS, Grande P, Sillesen H, Nordestgaard BG. Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med. 2008;359(18):1897.
  40. Zakai NA, Katz R, Jenny NS, Psaty BM, et al. Inflammation and hemostasis biomarkers and cardiovascular risk in the elderly: the Cardiovascular Health Study. J Thromb Haemost, June 2007; 5(6): 1125-1127.

Policy History:

Medical Policy Group, August 2002 (2)

Medical Policy Administration Committee, August 2002

Available for comment August 26-October 9, 2002

Medical Policy Group, September 2006 (1)

Medical Policy Group, September 2008 (1)

Medical Policy Group, September 2010 (1): Description updated, Key Points updated and Governing Bodies information added

Medical Policy Group, September 2012 (3): Active Policy but no longer scheduled for regular literature reviews and updates.

Medical Policy Group, October 2013 (3): Removed ICD-9 Diagnosis codes; no change to policy statement.

Medical Policy Group, June 2019 (9): Updates to Description, Key Points, References, and Approved by Governing Bodies. Added key words: ASCVD, Atherosclerotic cardiovascular disease. No change to intent of policy statement.


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.